Atopic Dermatitis (AD)

Home , Fezakinumab, Lebrikizumab, Tezepelumab, Tralokinumab

This activity is provided by PRIME Education. There is no fee to participate. This activity is supported by education grants from AbbVie, Inc., Sanofi Genzyme and Regeneron Pharmaceuticals. © 2019 PRIME® Education, LLC. All Rights Reserved..

Overview

This downloadable fact‐sheet provides an easy‐to‐follow collection of the latest evidence shaping the treatment and management of psoriasis (PsO) and atopic dermatitis (AD).

Learn about validated tools, evidence‐based strategies, and new and emerging targeted therapies that can be incorporated in daily practice to improve outcomes for patients with these conditions.

1 Learning Objectives

• Identify major barriers to evidence‐based treatment and management in federal and public sectors • Implement appropriate methods for diagnosis and assessment of disease activity • Assess current evidence on targeted biologic and small‐molecule therapies to guide treatment decisions for patients with moderate to severe disease • Monitor treatment responses according to treat‐to‐target principles and methods • Apply current evidence and guidelines to inform treatment decisions for patients with inadequate responses to initial therapies • Incorporate patient‐reported outcomes and shared decision‐making into clinical practice • Apply effective strategies for multidisciplinary care coordination and shared patient management

Accreditation

In support of improving patient care, PRIME® is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. This activity was planned by and for the healthcare team, and learners will receive 2.25 Interprofessional Continuing Education (IPCE) credits for learning and change. Physician Credit Designation Statement PRIME Education, LLC (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. PRIME® designates this Enduring material for a maximum of 2.25 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. Physician Assistant Credit Designation Statement PRIME® has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credits for activities planned in accordance with AAPA CME Criteria. This activity is designated for 2.25 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation.. Nurse Practitioner Credit Designation Statement PRIME® is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This activity is approved for 2.25 contact hours of continuing education (which includes 0.9 hours of pharmacology). Pharmacist Credit Designation Statement This Application‐based activity has been approved for 2.25 contact hours (0.225 CEUs) by PRIME® for pharmacists. The Universal Activity Number for this activity is JA0007144‐0000‐19‐087‐H01‐P. Pharmacy CE credits can be electronically submitted to the NABP upon successful completion of the activity. Pharmacists with questions can contact NABP customer service ([email protected]). Nurse Credit Designation Statement PRIME Education, LLC (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for 2.25 contact hours. © 2019 PRIME® Education, LLC. All Rights Reserved..

2 Disclosure Policy

PRIME Education, LLC (PRIME®) endorses the standards of the ACCME, as well as those of the AANP, ANCC, and ACPE, which require everyone in a position of controlling the content of a CME/CE activity to disclose all financial relationships with commercial interests related to the activity content. CME/CE activities must be balanced, independent of commercial bias, and designed to improve quality in health care. All recommendations involving clinical medicine must be based on evidence accepted within the medical profession. A conflict of interest is created when individuals in a position of controlling the content of CME/CE activities have a relevant financial relationship with a commercial interest which therefore may bias his/her opinion and teaching. This may include receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, stocks, or other financial benefits. PRIME® will identify, review, and resolve all conflicts of interest that speakers, authors, course directors, planners, peer reviewers, or relevant staff disclose prior to an educational activity being delivered to learners. Disclosure of a relationship is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Disclosure information for speakers, authors, course directors, planners, peer reviewers, and/or relevant staff is provided with this activity. Presentations that provide information in whole or in part related to non‐FDA‐approved uses of drugs and/or devices will disclose the unlabeled indications or the investigational nature of their proposed uses to the audience. Participants should refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. The opinions expressed in the educational activity are those of the presenting faculty and do not necessarily represent the views of PRIME®, ACCME, AANP, ACPE, ANCC, or other relevant accreditation bodies.

Faculty Disclosures

The following individuals have identified relevant financial relationships with commercial interests to disclose: • Laura K Ferris, MD, PhD (Lead Faculty) Advisory Board/Panel – Dermavant, Janssen Principal Investigator of Research Grant – AbbVie, Amgen, Celgene, Dermavant, Eli Lilly and Company, Janssen, Leo Pharma, Novartis • Grant W Cannon, MD (Lead Faculty) Principal Investigator of Research Grant – Amgen

The following individuals have no relevant financial relationships with commercial interests to disclose: • Heidi Wynn Maloni, PhD, ANP‐BC, CNRN, MSCN (Planner)

• Ryan Burke, PharmD (Planner)

• Mark A Rubin, MD (Reviewer)

All PRIME staff participating in planning and content development have no relevant financial relationships with commercial interests to disclose.

3 PSORIASIS

Unmet Needs in the Treatment and Management

4 Disease and Economic Burden of Psoriasis in the US

7.4 million Americans affected $ 112 – 135 billion per year

8 7.4 Annual Costs (2013) 7 6 Direct Indirect* Comorbidities 5 4 3 2.1 1.8 2 Millions of Adults 1 0.5 19% 0 Psoriasis Rheumatoid Atopic Crohn's 19% 62% Arthritis Dermatitis Disease

30% of patients with psoriasis have moderate‐to‐severe disease

*Indirect costs reflects loss of productivity (presenteeism and absenteeism). Rachakonda TD, et al. J Am Acad Dermatol. 2014;70(3):512‐516; Brezinski EA, et al. JAMA Dermatol. 2015;151(6):651‐658. © 2019 PRIME® Education, LLC. All Rights Reserved.. 9

Psoriasis is Associated with Multiple Comorbidities

Likely a result of the interplay between environmental and genetic factors, as well as overlapping inflammatory pathways

Rheumatologic Cardiovascular • ≈30% of patients with psoriasis develop psoriatic arthritis • ≈60% of patients with moderate‐severe psoriasis have ≥2 established CV risk factors* • ~41% of patients with PsA remain undiagnosed • 40–60% of patients do not receive optimal management for • Joint damage is irreversible and is present in half of patients cardiovascular comorbidities within 2 years of disease onset • Risk for cardiovascular outcomes increases with psoriasis severity and is independent of traditional CV risk factors

Other comorbidities include: metabolic syndrome, depression, Crohn's disease, cerebrovascular disease, and chronic pulmonary disease

PsA = Psoriatic Arthritis; CV = Cardiovascular; NCEP = National Cholesterol Education Program Adult Treatment Panel. *Established CV Risk factors based on NCEP criteria: men ≥45 years; women ≥55 years; diabetes and/or hypertension; fasting HDL‐C levels ≤40 mg/dL; family history of early coronary artery disease; current smokers. Yeung H, et al. JAMA Dermatol. 2013;149(10):1173–1179; Mehta NN, et al. Am J Med. 2011;124(8):775; Mehta NN, et al. Eur Heart J. 2010;31(8):1000–1006; Gelfand JM, et al. J Invest Dermatol. 2009;129(10):2411–2418; Gelfand JM, et al. JAMA. 2006; 296(14):1735–1741; Kimball AB, et al. J Am Acad Dermatol. 2012;67(1):76–85; McArdle A, et al. Clin Rev Allergy Immunol. 2017. Epub ahead of print; Mease PJ, et al. J Am Acad Dermatol. 2013;69(5):729–735; Ritchlin CT, et al. N Engl J Med. 2017;376(10):957–970. © 2019 PRIME® Education, LLC. All Rights Reserved.. 10

5 Presence of Comorbidities Increases Healthcare Costs for Patients with Psoriasis

114,512 adult patients with PsO identified through the IMPACT Database between 1999‐2004. About 50% of patients had ≥1 comorbidity of interest (below)

Adjusted Incremental Costs† Associated with Comorbidies $8,000.00 $6,191.00 $6,000.00 $5,280.00 $5,381.00

$4,000.00 $2,918.00 $2,823.00 $2,551.00 $2,184.00 $1,879.00 $2,000.00 $1,660.00

US Dollars (2007) $82.00 $‐

*Adjusted for age, sex, and psoriasis severity. † Costs include pharmacy, inpatient, emergency department, outpatient, and other medical services. PsO= psoriasis. PsA = psoriatic arthritis; CVD = cardiovascular disease; CBD = cerebrovascular disease; PVD = peripheral vascular disease. Kimball AB, et al. J Eur Acad Dermatology Venereol. 2011;25(2):157‐163. 11 © 2019 PRIME® Education, LLC. All Rights Reserved..

Treatment Patterns Among Psoriasis Patients

MAPPS Survey to Patients and Providers Treatment Use* by Psoriasis Severity • 735 psoriasis patients, 101 dermatologists, and 100% 100 rheumatologists surveyed in 2012 4% 5% 5% . 20% of patients had never seen a dermatologist for 8% Biologic +/‐ Topical their psoriasis 80% Oral + Biologic . 42% of patients go 1 year without visiting a HCP. 53% 60% 55% 52% Oral +/‐ Topical Medication Use per Health Plan Claims Data 40% Topical Only • 46,369 adults with moderate‐severe plaque Patients (%) psoriasis over a 5‐year period (2007‐2012) 20% 41% 32% 37% No Treatment . 32% diagnosed but never treated . 48% received but at some point discontinued 0% treatment Mild Moderate Severe (n = 2122) (n = 393) (n = 166) . 20% currently receiving treatment

* As reported by psoriasis patients from North America and Europe through the MAPPS Survey MAPP = Multinational Assessment of Psoriasis and Psoriatic Arthritis; HCP = health‐care provider. Lebwohl MG, et al. Am J Clin Dermatol. 2016;17:87‐97; Armstrong AW, et al. Dermatol Ther (Heidelb). 2017;7(1):97‐109; Lebwohl MG, et al. J Am Acad Dermatol. 2014;70(5):871‐881. © 2019 PRIME® Education, LLC. All Rights Reserved.. 12

6 Clinical Manifestation and Assessment

Psoriasis: Onset and Clinical Features

• Complex genetic disease with environmental triggers Most Frequently‐Experienced Symptoms . Stress Other 5% . Infections . Smoking and alcohol Fatigue 19% . Physical trauma Burning Sensation 21% . Drugs (e.g., lithium, beta‐blockers) • Age of Onset Bleeding 29% Age Peak Onset Tightness of Skin 31% <40 years old 16–22 years Skin Redness 71% >40 years old Mid‐to‐late 50s Itching 79%

• Psoriatic plaques Scaling 94% . Erythema (redness) . Induration (thickness) 0% 20% 40% 60% 80% 100% . Desquamation (scaling) Percentage of Respondents

7 Variants of Psoriasis

Plaque (vulgaris) Guttate Nail Pustular

Scalp Palmar‐Plantar Erythrodermic Inverse

Distinguishing Features and Differential Diagnosis

Differential Diagnosis Distinguishing Clinical Features

• Predominant symptom: pruritus • Typical morphology and distribution: Atopic dermatitis o Flexural lichenification in adults/older children o Facial and extensor papules and vesicles in infants

Contact dermatitis • Patches or plaques with angular corners, geometric outlines, and sharp margins

• Violaceous lesions Lichen planus • Frequent mucosal involvement

• Copper‐colored lesions Secondary syphilis • Frequent involvement of palms and soles

Mycosis fungoides • Irregularly shaped lesions with asymmetric distribution; wrinkling due to atrophy Tinea corporis • Fewer lesions with annular configuration

• Tannish‐pink, oval papules, and patches with “Christmas tree” configuration on trunk Pityriasis rosea • Sparing of the face and distal extremities

8 Assessing Psoriasis Severity

Body Surface Area (BSA) Psoriasis Area Severity Index (PASI) • Used primarily in clinical practice • Used primarily in clinical trials 1 • 1 palm = 1% of your BSA • Scaling score domains: . Mild: 1–3% . Severity (0 – 4) of the psoriatic 2 3 2 . Moderate: 3–10% plaques elements: . Severe: ˃10% • Erythema (redness) • Induration (thickness) • Location also • Desquamation (scaling) determines severity . Surface area (0–6 based on %) 44 . Scalp in each body region . Hands and feet • PASI score ≥10 is considered . Groin and skin folds moderate to severe disease

Other disease assessment scores include the PGA, EQ‐5D, SF‐36, DLQI, and PQL/PDI

PGA = Physician’s Global Assessment; EQ‐5D= EuroQoL 5 dimensions; SF‐36 = Short‐Form Health Survey; DLQI = Dermatology Life Quality Index; PQL/PDI = Psoriasis Quality of Life, Psoriasis Disability Index. Feldman SR, et al. Ann Rheum Dis. 2005;64(Suppl II):ii65‐ii68; Carlin CS, et al. J Am Acad Dermatol. 2004;50(6):859–866; Fredriksson T, et al. Dermatologica. 1978;157(4):238–244. © 2019 PRIME® Education, LLC. All Rights Reserved.. 17

PASI and BSA Images

Mild Moderate Severe BSA 1–3% BSA 3–10% BSA >10% PASI <10 PASI 10–15 PASI >15

9 Considerations for Determining Psoriasis Severity

Extent of Disease Location & Type of Lesions Degree of Inflammation

Response to Treatment Impact on Quality of Life Presence of Comorbidities

Physical and Mental Impact of Psoriasis Compared to Other Diseases

1. Healthy adults 1. Healthy adults 2. Dermatitis 2. Hypertension 3. Cancer 3. Type 2 diabetes 4. Depression 4. Myocardial infarction 5. Hypertension 5. Congestive heart failure 6. Arthritis 6. Cancer 7. Myocardial infarction 7. Arthritis 8. Chronic lung disease 8. Dermatitis 9. Type 2 diabetes 9. Psoriasis Physical Component Mental Component 10.Psoriasis 10. Chronic lung disease 11. Congestive heart failure 11. Depression

10 Guidelines and Evidence for Evolving Treatment Strategies

What Does Optimal Treatment Response Look Like?

PGA 4 (PASI 20) PGA 3(PASI 12) PGA 2 (PASI 5) PASI 75 RESPONSE

PGA 1 (PASI 3) PGA 0 (PASI 0) PASI 100 RESPONSE

11 National Psoriasis Foundation’s Treat to Target Guidance

NPF consensus to define treatment goals for US providers Help patients and providers make treatment decisions, reduce disease burden, and improve quality of life Time Target Acceptable BSA ≤3% 3 months after treatment initiation BSA ≤1% or BSA improvement ≥75% from BL

Every 6 months maintenance evaluation BSA ≤1%

What challenges does your team face in implementing treat‐to‐target approaches for patients with psoriasis?

Higher PASI Response Leads to Higher QoL Improvements

Pooled Data from the FIXTURE and ERASURE Phase 3 Trials • Treatment Arms – Secukinumab 300mg (n = 572) 100 76 75 74 – Secukinumab 150mg (n = 572) 80 69 59 59 60 55 57 – Etanercept (n=326) 47 46 47 41 36 40 31 • Measuring DLQI Response 26 29 20 16 13 – Ranges from 0–30, higher scores DLQI responders (%) indicate greater impairment 0 – Response: total score of 0/1 Week 4 Week 8 Week 12 Week 24 Week 36 Week 52 PASI 90–100 PASI 75–89 PASI <75 Higher PASI scores were also associated with lower percentages of weekly work impairment and lower average of hours lost PASI <50: 7.60 hours; PASI 50–74: 4.45 hours; PASI 75–89: 2.14 hours; PASI ≥90: 1.65 hours. DLQI = Dermatology Life Quality Index. Elewski BE, et al. J Dermatolog Treat. 2017;28(6):492–499; Warren RB, et al. J Eur Acad Dermatol Venereol. 2018. Epub ahead of print. © 2019 PRIME® Education, LLC. All Rights Reserved.. 24

12 AAD Guidelines for the Treatment of Psoriasis (2008)

Psoriasis PsO + PsA Anti‐TNF± MTX Biologic/Small Molecule 2015 GRAPPA Apremilast* Recommendations: Adalimumab Biologic or PDE4i Etanercept Infliximab Ustekinumab Extensive Secukinumab* disease Ixekizumab* Brodalumab* Limited Traditional Systemic Therapy Guselkumab* disease Methotrexate Biosimilars* Cyclosporine Tildrakizumab‐asmn* Ultraviolet Light/Lasers Acitretin Certolizumab pegol* Ultraviolet B Risankizumab‐rzaa* Photochemotherapy Topical Therapy OTC Moisturizers Treatment Lack of Effect? Cortisone/steroid creams Escalation Calcipotriene

*Approved after publication of guidelines. AAD = American Academy of Dermatoloy; MTX = Methotrexate; GRAPPA = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; PsO = Psoriasis; OTC = Over the Counter. Menter A, et al. J Am Acad Dermatol. 2008 May;58(5):826–850; Menter A, et al. J Am Acad Dermatol. 2011 Jul;65(1):137–174; Coates LC, et al. Arthritis Rheumatol. 2016;68(5):1060–1071. © 2019 PRIME® Education, LLC. All Rights Reserved.. 25

Traditional Systemic Agents for Psoriasis

Treatment Type Administration Benefits Limitations

• Contraindications include alcohol abuse, cirrhosis, fatty liver disease, active infectious DHFR‐ • Effective for long‐term Methotrexate Oral/SC QW disease, pregnancy, and renal impairment inhibitor continuous use • Use with caution with NSAIDS and certain antibiotics • Use should not exceed 3–6 months due to permanent kidney damage Calcineurin • Effective intermittent Cyclosporine Oral QD • Potential to cause hypertension and certain therapy for flare‐ups inhibitor malignancies • Several potential drug interactions • Significant side effects limit long‐term use • Less risk of specific end‐ Acitretin Retinoid Oral QD organ toxic effects • Contraindicated in pregnancy or in women intending to get pregnant

NPF = National Psoriasis Foundation; DHFR = dihydrofolate reductase; QD = Once a Day; QW = Once a Week; SC = Subcutaneous. NPF. Traditional Systemic Medications. https://www.psoriasis.org/about‐psoriasis/treatments/systemics. Accessed 9/21/17; Hsu S, et al. Arch Dermatol. 2012;148(1):95–102; Bilal J, et al. Am J Med. 2018. Epub ahead of print. 26 © 2019 PRIME® Education, LLC. All Rights Reserved..

13 Pathophysiological Mechanisms that Underpin Psoriasis

Cycle maintained with: IL‐1 β, IL‐6, TNF, chemokines Keratinocyte activation and proliferation Skin Stress

PDE‐4 Etanercept IL‐2 IL‐17A IL‐1 β Infliximab IL‐17A IF‐N γ IL‐17F IL‐6 Adalimumab IL‐17F TNF Certolizumab pegol TNF Brodalumab IL‐22 Apremilast Secukinumab Ustekinumab TH17 Ixekizumab Tc17 Th17 TH1 Tc1 IL‐23 Th17 IL‐12 Dermal DC Th2

T‐naïve Tildrakizumab‐asmn Guselkumab Macrophage Lymph node Risankizumab‐rzaa

Green indicates therapies that have been approved by the FDA for the treatment of Psoriasis. Image adapted from Gaspari AA, et al. Dermatol Ther. 2015;28(4):179–193. © 2019 PRIME® Education, LLC. All Rights Reserved.. 27

FDA‐ Approved Biologic and Small Molecule Therapies for Moderate to Severe Psoriasis

Therapy Target Approval Key Trial Route Initial Dosing* Maintenance* Apremilast PDE‐4 2014 ESTEEM 1 Oral Titrate up +10 mg 30 mg BID Etanercept TNF‐ɑ 2004 Leonardi 2003 SC 50mg twice per week 50mg QW Infliximab TNF‐ɑ 2006 EXPRESS 1 IV 5 mg/kg at weeks 0, 2, and 6 5 mg/kg Q8W Adalimumab TNF‐ɑ 2008 REVEAL SC 80mg at week 0 40mg Q2W Certolizumab Pegol TNF‐ɑ 2018 CIMPASI 1/2 SC ‐ 400mg Q2W Ustekinumab IL‐12 / IL‐23 2009 PHOENIX 2 SC 45mg/90mg at weeks 0 and 4 45mg/90mg Q12W Secukinumab IL‐17A 2015 FIXTURE SC 300mg at weeks 0, 1, 2, 3 and 4 300mg Q4W 160mg at week 0, then Ixekizumab IL‐17A 2016 UNCOVER 1 SC 80mg Q4W 80mg Q2W until week 12 Brodalumab IL‐17A‐R 2017 AMAGINE 3 SC 210mg at weeks 0, 1, and 2 210 Q2W Guselkumab IL‐23 2017 VOYAGE 3 SC 100mg at weeks 0 and 4 100mg Q8W Tildrakizumab‐asmn IL‐23 2018 reSURFACE 1 SC 100mg at weeks 0 and 4 100mg Q12W Risankizumab‐rzaa IL‐23 2019 UltIMMa 1/2 SC 150 mg at weeks 0 and 4 150 mg Q12W

*For adult patients; refer to prescribing information for accurate dosing based on age, weight, or other patient factors. Papp K, et al. J Am Acad Dermatol. 2015;73(1):37–49; Leonardi CL, et al. N Engl J Med. 2003;349(21):2014–2022; Reich K, et al. Lancet. 2005;366(9494):1367–1374; Menter A, et al. J Am Acad Dermatol. 2008;58(1):106–115; Papp KA, et al. Lancet. 2008;371(9625):1675–1684; Langley RG, et al. N Engl J Med. 2014;371(4):326–338; Gordon KB, et al. N Engl J Med. 2016;375(4):345–356; Lebwhol M, et al. N Engl J Med. 2015;373(14):1318–1328; Reich K, et al. J Am Acad Dermatol. 2017;418–431; Reich K, et al. Lancet. 2017; 390(10091):276–288. 28 © 2019 PRIME® Education, LLC. All Rights Reserved..

14 PASI 90 and 100 Response Rates in Biologics Approved After 2014

Please note: data presented in this graph come from different trials and are not directly comparable. 90 80 Risankizumab‐rzaa 180 mg: Wk 16 (n = 42) 80 77 70 69 70 70 Tildrakizumab‐asmn 200 mg: Wk 12 (n = 308)

60 55 Guselkumab 100 mg: Wk 16 (n = 496) 50 45

40 37 37 35 34 Brodalumab 210 mg: Wk 12 (n = 629) Patient Response (%) 30 Ixekizumab 80 mg: Wk 12 (n = 1169) 20 14 10 Secukinumab 300 mg: Wk 16 (n = 550) 0 PASI 90 PASI 100

Papp KA, et al. Dermatol Ther. 2017;30(5):1551‐1560; Reich K, et al. Lancet. 2017;390(10091):276‐288; Reich K, et al. J Am Acad Dermatol. 2017;76(3):418‐431; Lebwohl M, et al. N Engl J Med 2015;373:1318‐28; Papp KA, et al. Br J Dermatol. 2018;178(3):674‐681; Bagel J, et al. Dermatol Ther (Heidelb). 2018;8(4):571‐579; © 2019 PRIME® Education, LLC. All Rights Reserved.. 29

Apremilast in Moderate to Severe Plaque Psoriasis: Results from ESTEEM 1 and 2

• Efficacy PASI‐75 Response at Week 16 . PASI response was maintained over 52 weeks 50 Placebo Apremilast 30 mg BID . Improvements in both nail and scalp psoriasis 40 • Safety 33% . AEs did not increase with long term use 30 29% (≥156 weeks) . Most common AEs: diarrhea, nausea, upper 20 respiratory tract infection, nasopharyngitis, and headache 10 . Use may result in significant weight loss, as 5% 6% Patients Achieving Response (%) well as depression N= 282 562 137 274 0 . Drug interactions common ESTEEM 1 ESTEEM 2

AEs = adverse events. Papp K, et al. J Am Acad Dermatol. 2015;73(1):37–49; Paul C, et al. Br J Dermatol. 2015;173(6):1387–1399; Rich P, et al. J Am Acad Dermatol. 2016;74(1):134–142; Crowley J, et al. J Am Acad Dermatol. 2017;77(2):310–317.e1; OTEZLA® (apremilast) [package insert]. Celgene Corporation. Summit, NJ. June 2017. © 2019 PRIME® Education, LLC. All Rights Reserved.. 30

15 Efficacy and Safety of Adalimumab vs Methotrexate in Patients with Psoriasis: CHAMPION Phase 3 Study PASI Improvement PGA 0 or 1 Placebo Methotrexate Adalimumab 100% Placebo Methotrexate Adalimumab 100% * * ** * 81% 81% 80% 80% 74% * 81% 81% 74% 57% 60% * 54% 60% 54% 57% 49% 49% 40% 36% 40% 36% 22% 22% 20% 21% 22% 20% 20% 15% 15% 20% 21% 22% 0% 0% Patients with PGA of 0 or 1 Mean % PASI Improvement 0 4 8 12 16 4 8 12 16 Weeks Weeks Placebo (n = 53) Methotrexate (n = 110) Adalimumab (n = 107) Total AEs 79% 82% 74% Serious AEs 2%1%2% AE‐related discontinuations 2% 6% 1% Most common AEs in the adalimumab group: non‐serious infections, nasopharyngitis, headache, and arthralgia.

* P<0.001 vs placebo and P<0.001 vs methotrexate. Adalimumab was administered as 80mg SC at week 0, then 40 mg Q2W; oral MTX was administered as a single dose, starting at 7.5 mg per week at week 0, and then increased according to regimen up to 25mg per week. Saurat JH, et al. Br J Dermatol. 2008;158(3):558–566. © 2019 PRIME® Education, LLC. All Rights Reserved.. 31

Pooled Efficacy and Safety of Certolizumab Pegol in Psoriasis: CIMPASI‐1 and ‐2 Phase 3 Trials

Pooled Outcomes at Week 16 Additional Outcomes

Placebo (n = 100) CZP 200mg Q2W (n = 186) CZP 400mg Q2W (N = 175) • Outcomes at Week 48 100% . PASI 75 and PGA 0/1 rates were maintained for both CZP treatment groups 82% 80% 77% . Patients with prior anti‐TNF use held similar responses * * 65% to those without prior anti‐TNF exposure 60% 57% * • Safety profile * . Most common TEAE among CZP‐treated patients: 40% nasopharyngitis and upper respiratory tract infection Patients (%) . Safety profile consistent with anti‐TNF therapy 20% 10% CRIB & CRADLE Trials: 3% • CZP is compatible with pregnancy and lactation 0% • FDA‐approved for pregnant and breastfeeding PASI 75 PGA 0/1 women (2018)

* P<0.0001 vs placebo. CZP = Certolizumab Pegol; PGA = Physician’s Global Assessment; TEAE = Treatment‐Emergent Adverse Events. Gottlieb AB, et al. J Am Acad Deramatol. 2018. Epub ahead of print; Mariette X, et al. Ann Rheum Dis. 2018;77(2):228‐233; Clowse ME, et al. Ann Rheum Dis. 2017;76(11):1890‐1896. © 2019 PRIME® Education, LLC. All Rights Reserved.. 32

16 Efficacy and Safety of Secukinumab vs Etanercept Over 52 Weeks: FIXTURE Study

100 PASI 75 Secukinumab Secukinumab Etanercept Placebo 80 Adverse Events† 300mg 150mg (n = 467) (n = 469) (n = 323) (n = 327) 60 Any 252 236 243 330 40 Serious 7678 20 Infections 105 92 91 90

Patients with Response (%) 0 Common 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Nasopharyngitis 35 31 36 33 100 PASI 100 SECU 300mg Q4W* (n = 323) SECU 150mg Q4W* (n = 327) Headache 16 12 15 30 80 ETN 50mg QW* (n = 323) Diarrhea 10 9 8 8 60 Placebo (n = 324) Pruritus 45613 40 Arthralgia 69812 Discontinuation 20 14 10 12 3 due to AE 0

Patients with Response (%) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks *Secukinumab was administered QW from weeks 0–4, and then Q4W from weeks 4–48. Etanercept was given twice weekly from week 0–12, and then QW from week 12–51. †Number of cases per 100 paent‐years (exposure‐adjusted incidence rates). Langley RG, et al. N Engl J Med. 2014;371(4):326–338. © 2019 PRIME® Education, LLC. All Rights Reserved.. 33

Efficacy & Safety of Ixekizumab vs Etanercept: UNCOVER Phase 3 Trials PASI‐75 Response (Week 0–12) PASI‐75 Response by Prior Biologic Use UNCOVER 2 UNCOVER 3 100 UNCOVER 2 89 93 IXE 80mg Q2W* (n = 351) IXE 80mg Q2W* (n = 385) 100 100 Naïve 79 IXE 80mg Q4W* (n = 347) IXE 80mg Q4W* (n = 386) 80 74 ETN 50mg† (n = 358) ETN 50mg† (n = 382) Experienced PBO (n = 168) PBO (n = 193) 60 45 50 50 40 30

20 Patients (%) Patients (%) 3 0 0 0 0 0246810 0246810 Weeks Weeks PBO ETN* IXE Q4W* IXE Q2W

AEs (%) Placebo (n = 360) ETN (n =739) IXE Q4W (n = 729) IXE Q2W (n = 734) Any TEAE 44% 54% 58% 58% Any Infection 21% 22% 26% 3+% Nasopharyngitis 8% 7% 8% 8% URTI 3% 5% 3% 4% Injection Site Reactions 1% 11% 9% 10%

*Both ixekizumab groups received an inial dose of 160mg at baseline. †Etanercept 50mg was given twice weekly. ETN = Etanercept; IXE = Ixekizumab; PBO = Placebo; Q2W = Every 2 Weeks; Q4W = Every 4 Weeks; URTI = Upper Respiratory Tract Infection. Griffiths CE, et al. Lancet. 2015;386(9993):541–551; TALTZ® (ixekizumab) [package insert]. Eli Lilly and Company. Indianapolis, IN. March 2016. © 2019 PRIME® Education, LLC. All Rights Reserved.. 34

17 Efficacy & Safety of Brodalumab vs Ustekinumab in Psoriasis

AMAGINE 2 Study Brodalumab PASI 75 PASI 100 Placebo 210mg Q2W Ustekinumab 86% Common (n = 879) (n = 1,496) (n = 613) Adverse Events % % % 70% Arthralgia 3.3 4.7 2.4 67% 44% Headache 3.5 4.3 3.8

26% Fatigue 1.1 2.6 2.6

Response Rate (%) 8% 22% Diarrhea 1.1 2.2 0.8 1% Nausea 1.1 1.9 1.0 Week Week Myalgia 0.3 1.7 0.7 Brodalumab 210 mg Q2W (n = 612) Ustekinumab 45/90mg* Q12W (n = 300) Injection Site 1.3 1.5 2.0 Brodalumab 140mg Q2W (n = 610) Placebo (n = 309) Reactions

Suicidal ideation and behavior was reported in the clinical studies of brodalumab. Prescribers are required by FDA to counsel patients about this risk and patients are required to sign the risk acknowledgement form *Ustekinumab was given at 45mg for patients with a body weight under 100kg, and 90mg for patients with a body weight over 100kg. Ustekinumab was given at week 0, then at week 4, and then Q12W thereafter. Lebwohl M, et al. N Engl J Med. 2015;373(14):1318–1328; SILIQ® (brodalumab) [package insert]. Valeant Pharmaceuticals. Bridgewater, NJ. February 2017; Roman M, Chiu MW. Drug Des Devel Ther. 2017;11:2065‐ 2075. © 2019 PRIME® Education, LLC. All Rights Reserved.. 35

Efficacy of Guselkumab vs Adalimumab in Psoriasis: VOYAGE 2 Phase 3 Trial

Active‐Comparator Period (Week 0–24) Safety Events Guselkumab Adalimumab PASI 75 PASI 100 Weeks 0–48 (n = 494) (n = 248) 100 100 * ≥1 AE 58% 63% 80 80 ≥1 Serious AE 4% 4% Common AE 60 60 Nasopharyngitis 10% 14% * Headache 6% 4% 40 40 URTI 5% 4% Patients (%) 20 20 AE‐related discontinuations (n) 11 6

0 0 Infections 31% 35% 2 4 8 12 16 20 24 2 4 8 12 16 20 24 Week Week Switching Adalimumab Nonresponders to Guselkumab Guselkumab 100mg Q8W† (n = 496) • 112 adalimumab NR initiated guselkumab at Week 28 Adalimumab 40mg Q2Wⱡ (n = 248) • Response rates after switching at Week 48: o PASI‐75: 66.1% *P<0.001 o PASI‐100: 28.6% †Guselkumab was administered at weeks 0, 4, 12, and 20. ⱡ Adalimumab 80mg was given at week 0, then 40mg at week 1, and then 40mg Q2W thereafter. R = Responders; NR = Non‐Responders. Reich K, et al. J Am Acad Dermatol. 2017;76(3):418–431. © 2019 PRIME® Education, LLC. All Rights Reserved.. 36

18 Tildrakizumab vs Placebo or Etanercept in moderate to severe Plaque Psoriasis: reSURFACE 1 and 2 Phase 3 Trials PASI‐75 Response 100 TIL ETN reSURFACE 1 reSURFACE 2 Pooled† Adverse Placebo 100mg 50mg Events (n = 355) 80 (n = 705) (n = 313)

Treatment‐Emergent 48% 54% 54% 60 Treatment‐Related 15% 29% 13% 40 Serious1%2%2%

20 Injection site 3% 18% 2% reactions 0 0 4 8 12 16 22 28 0 4 8 12 16 22 28 Discontinuations (n) 464 Weeks Weeks Tildrakizumab 100mg* Placebo to Tildrakizumab 100mg Etanerceptⱡ 50mg Severe infections (n) 101 Tildrakizumab 200mg* Placebo to Tildrakizumab 200mg Malignancies (n) 210 *Tildrakizumab 200mg and 100mg doses were given at baseline and week 4, then given Q12W. ⱡOnly in reSURFACE 2. Etanercept 50mg was given twice a week through weeks 0–12, then QW through week 28. †Includes data from Phase 2 Trial (NCT01225731). TIL = Tildrakizumab. Reich K, et al. Lancet. 2017;390(10091):276–288; Blauvelt a, et al. Br J Dermatol. 2018. Epub ahead of print. © 2019 PRIME® Education, LLC. All Rights Reserved.. 37

Efficacy and Safety of Risankizumab‐rzaa in Psoriasis: IMMvent and IMMhance Phase 3 Trials

IMMvent: Efficacy vs Adalimumab IMMhance: Withdrawal and Retreatment Patients were dosed with Risankizumab at weeks 0 and 4 100 Treatment Withdrawal Retreatment Risankizumab (n = 301) Adalimumab (n = 304) relapsed 80 72 RZB responders RZB 65 Wk 28 PBO Wk 32 RZB

60 47 38 41 RZB (n = 111) RZB→PBO (n = 225) RZB→PBO→RZB (n = 153) 40 100% 81% 84% Patients (%) 20 80% 6 26 0 60% 0 5

Patients Wk 16 after 0481216 40% Wk 102 Wk 102 retreatment Number at Risk Week 20% 7% Adalimumab 0 18 79 126 144 Risankizumab 0 19 115 197 218 0% sPGA 0 or 1 (Week 102)

• Risankizumab was superior in efficacy to adalimumab in psoriasis treatment and its response was continuously seen throughout the 44‐week study (IMMvent) • Proportion of patients with any TEAE was similar across treatment groups

PASI = Psoriasis Area and Severity Index; sPGA = static Physician Global Assessment; RZB = Risankizumab; PBO = Placebo; Wk = week; TEAE = Treatment‐Emergent Adverse Events Gordon KB, et al. Lancet. 2018;392(10148):650–661; Langley RG, et al. AAD 2019; Washington, DC. Abstract 10093; Blauvelt A., et al. World Congress of Dermatology 2019; Milan, Italy. Late‐breaking Abstract. © 2019 PRIME® Education, LLC. All Rights Reserved.. 38

19 Emerging Biologic and Small Molecule Therapies for Moderate to Severe Psoriasis

Treatment Administration Target Phase 3 Trials (NCT#) BE SURE (NCT03412747) Bimenkizumab SC injection IL‐17A/F BE READY (NCT03410992) BE VIVID (NCT 03370133)

POETYK‐PSO‐1 (NCT03624127) BMS‐986165 Oral TYK2 POETYK‐PSO‐2 (NCT03611751) LAS41008 Oral NFE2L2 pathway BRIDGE (NCT01726933) (dimethyl fumarate) (NCT03168256) Piclidenoson (CF101) Oral adenosine A3 receptor (NCT01265667) OASIS‐1 (NCT03482011) Mirikizumab SC injection IL‐23 OASIS‐2 (NCT03535194) OASIS‐3 (NCT03556202)

Screening for Joint Symptoms

20 Screening Tools for Detecting PsA

Sensitivity % Specificity % Tool Item Topics Number of Items Range Range

97% 79% PEST Joint or skin manifestations (present or ever) 5 items + joint diagram 0.28–0.77 0.37–0.98

82% 73% PASE PROs including pain, fatigue, mobility, productivity 15 items 0.24–0.75 0.39–0.94

ToPAS Joint/skin manifestations and family history 11 items + pictures/ diagrams 87% 93%

CONTEST Combines PEST, PASE, and ToPAS 12 items + joint diagram 38%–86% 35%–89%

*Patients with lower PsA disease activity, fewer disease features, shorter disease duration, or other types of musculoskeletal disease. PEST = Psoriasis Epidemiology Screening Tool; PASE = Psoriatic Arthritis Screening and Evaluation; ToPAS = Toronto Psoriatic Arthritis Screening Questionnaire. Raychaudhuri SP, et al. J Autoimmun. 2017;76:21–37; Ogdie A, et al. Rheum Dis Clin North Am. 2015;41(4):545–568. © 2019 PRIME® Education, LLC. All Rights Reserved.. 41

The Psoriasis Epidemiology Screening Tool (PEST) Questionnaire

YES NO Have you ever had a swollen joint (or joints)? Has a doctor ever told you that you have arthritis? Do your fingernails or toenails have holes or pits? Have you had pain in your heel? Have you had a finger or toe that was completely swollen and painful for no apparent reason?

Score /5

PEST score ≥3 is an indication for referral to a rheumatologist (UK NICE guidelines)

NICE = National Institute for Health and Care Excellence Ibrahim GH, et al. Clin Exp Rheumatol. 2009;27(3):469–474; NICE. Psoriasis: Assessment and Management. Available at www.nice.org.uk. Accessed 4/18/18. © 2019 PRIME® Education, LLC. All Rights Reserved.. 42

21 ATOPIC DERMATITIS

Disease Burden and Unmet Needs

22 Atopic Dermatitis (AD) is a Serious, Chronic Inflammatory Disease

• Chronic, relapsing, pruritic inflammatory skin disease • Results from complex interactions between genetic and environmental factors • Exact cause is unknown • Estimated prevalence in the US: . Up to 18% in children . Up to 10% in adults • Results in: . Decreased skin barrier function . Complex immune dysregulation

Images courtesy of Eric Simpson, MD. Barbarot S, et al. Allergy. 2018;73(6):1284–1293; Chiesa Fuxench ZC, et al. J Invest Dermatol. 2018. [Epub ahead of print]; Silverberg JI, et al. J Allergy Clin Immunol. 2013;132(5):1132–1138; Shaw TE, et al. J Invest Dermatol. 2011;131(1):67–73; Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338–351; Kim JE, et al. Int J Mol Sci. 2016;17(8):pii: E1234. © 2019 PRIME® Education, LLC. All Rights Reserved.. 45

Severity of AD in Children and Adults

Children (≤17 years) 10% to 30% Adult (≥18 years)

Onset of AD: More likely to persist to No direct estimates of prevalence of • 60% by 1 year of age adulthood if: moderate to severe AD • 90% by 5 years of age Later onset (after age 2 years) Extrapolation from other findings: Prevalence of disease More severe disease • 25% of adults with eczema do not severity (2007 NSCH): Already persistent disease see a physician for eczema (2010 • 67% mild (5.6M) NHIS) • 26% moderate (2.2M) • 0.7–1.2 million patients with severe • 7% severe (0.6 M) AD receive treatment

M = millions; NHIS = National Health Interview Survey; NSCH = National Survey of Children’s Health. Silverberg JI, et al. J Allergy Clin Immunol. 2013;132(5):1132–1138; Silverberg JI, et al. J Invest Dermatol. 2015;135(1):56–66; Silverberg JI, et al. Dermatitis. 2014;25(3):107–114; Kim JP, et al. J Am Acad Dermatol. 2016;75(4):681–687; Brown SJ, et al. J Invest Dermatol. 2012;132(3):751–762; Silverberg JI, et al. Pediatr Allergy Immunol. 2013;24(5):476–486; Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338–351. © 2019 PRIME® Education, LLC. All Rights Reserved.. 46

23 Intense and Persistent Itch Contributes Greatly to AD Disease Burden

Daily • 88% reported daily presence of itch

Long Lasting • 69% reported itching lasting at least 12 hours a day

Severe • 69% had severe or unbearable itching

Chronic • 55% reported itching for at least 10 years

Frequent • 40% had ˃10 episodes of itch per day

Pain • 50% reported pain sensation associated with itch

• 90% had at least 1 night of disrupted sleep per week Disrupted Sleep • 50% had at least 5 nights of disrupted sleep per week

Simpson EL, et al. J Am Acad Dermatol. 2016;74(3):491–498; Dawn A, et al. Br J Dermatol. 2009;160(3):642–644; O’Neill JL, et al. Acta Derm Venereol. 2011;91(5):537–540. © 2019 PRIME® Education, LLC. All Rights Reserved.. 47

Impact of AD on Quality of Life

• High rates of • Increased risk of • Sleep disruption depression and o Psychological anxiety disorders • Mental health o Motor vehicle • Major impact on accidents • Lost work/school days self‐esteem and social o Workplace injury functioning • Social isolation • Impacts performance at work/school Sleep Disturbances Family/Caregiver Psychological Distress Among skin diseases, AD has the 4th highest QOL‐related costs

Bickers DR, et al. J Am Acad Dermatol. 2006;55(3):490–500; Simpson EL, et al. J Am Acad Dermatol. 2016;74(3):491–498; Zuberbier T, et al. J Allergy Clin Immunol. 2006;118(1):226–232; Silverberg JI, et al. J Invest Dermatol. 2015;135(1):56–66; Drucker AM, et al. J Invest Dermatol. 2016;136(11):e109–e114. © 2019 PRIME® Education, LLC. All Rights Reserved.. 48

24 Relationship Between Prevalence of Mental Health Disorders and AD Severity

Data from the 2007 National Survey of Children’s Health (NSCH) Frequency of Mental Health Outcome Based on AD Status None Mild Moderate Severe 30% 28% 23% 20% 16% 14% 13% 13% 11% 9% 10% 8% 7% 8% 5% 5% 6% 5% Frequency (%) 4% 3% 4% 1% 3% 0% ADHD* Anxiety Depression Conduct Disorder* Autism* • AD children received more mental health therapy than peers without AD • Nights of adequate sleep decreased with increasing eczema severity

*Relationship between AD severity and mental health outcomes remained significant after adjusting for known confounders (eg. sex, age, ethnicity/race, household income, family size). ADHD = Attention Deficit Hyperactivity Disorder. Yaghmaie P, et al. J Allergy Immunol. 2013;131(2):428–433. © 2019 PRIME® Education, LLC. All Rights Reserved.. 49

Disease Assessment

25 AAD 2014 Guidelines: Diagnostic Criteria

Essential Features Important and Associated Features • Pruritus • Atopy • Eczema (acute, subacute, chronic) • Early age of onset • Typical morphology and age‐specific • Personal and/or family history patterns: • Immunoglobulin E (IgE) reactivity . Facial, neck, and extensor involvement in • Xerosis infants and children . Current or previous flexural lesions in any age • Atypical vascular responses* group • Ocular/periorbital changes . Sparing of the groin and axillary regions • Other dermatological features: • Chronic or relapsing pattern . Keratosis pilaris/ pityriasis alba/ hyperlinear palms/ icthyosis . Perifollicular accentuation/ lichenification/ *e.g., facial pallor, white dermographism, delayed blanch response. AAD = American Academy of Dermatology. prurigo lesions Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338–351. © 2019 PRIME® Education, LLC. All Rights Reserved.. 51

Clinical Features of AD

Erythema Xerosis/scaling Dyspigmentation

Papules/Spongiotic Vesicles Excoriations Lichenification

26 Differential Diagnoses to Consider in Pediatric and Adult Patients with Severe AD Condition Clinical features Children Adults Diagnostic work‐up  Patch testing for allergic Contact dermatitis (irritant or allergic) Atypical or localized distribution  contact Less pruritis and lack of eczematous change  Severe, suberythrodermic psoriasis Biopsy (oozing/crusting) Lack of pruritis with greasy scale in scalp and folds  Severe seborrheic dermatitis Clinical diagnosis in infants Inguinal, axillary, and genital papules;  Scabies infestation Mineral oil scraping palmoplantar vesicles and burrows in infants Annular papulosquamous lesions without Skin scraping for Widespread tinea corporis eczematous change microscopy and culture  Zinc levels and genetic Zinc deficiency Erosive plaques on face and groin with fussiness testing Erythroderma, hair abnormalities, and failure to  Netherton syndrome/other ichthyoses Genetic testing thrive Immune deficiencies (hyperIgE syndrome,  Sinopulmonary infections and failure to thrive Genetic testing severe combined immunodeficiency) Lack of classic eczematous skin changes, such as  Skin biopsy and T‐cell Cutaneous T‐cell lymphoma oozing or crusting rearrangement studies

Assessing Disease Severity

• There are over 25 tools that can be used to assess disease severity; however, they are rarely used in clinical practice • Best practice: combine clinical tools with patient interview questions to assess impact of AD on daily activity

Most commonly used Most commonly used disease‐severity scales: QOL measures: SCORAD CDLQI EASI DFI IGA DLQI SASSAD POEM IDQOL

SCORAD = SCORing Atopic Dermatitis; EASI = Eczema Area and Severity Index; IGA = Investigator Global Assessment; SASSAD = Six Area, Six Sign Atopic Dermatitis; POEM = Patient‐Oriented Eczema Measure; CDLQI = Children's Dermatology Life Quality Index; DFI = Dermatitis Family Impact; DLQI = Dermatology Life Quality Index; IDQOL = Infant's Dermatitis Quality of Life. Charman CR, et al. Arch Dermatol. 2004;140(12):1513–1519; Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338–351; Rehal B, et al. PLoS One. 2011;6(4):e17520.© 2019 PRIME® Education, LLC. All Rights Reserved.. 54

27 AD Disease and Symptom Severity Scales

Clinical Signs Disease Subjective Common Scale Edema/ Oozing/ Dryness/ Extent Erythema Excoriation Lichenification Symptoms End Point Papulation Crusts Scaling (BSA)

SCORAD‐50 SCORAD    % pts with 50% ↓ EASI‐50 EASI     % pts with 50% ↓

% pts with IGA IGA  0 (clear) or 1 (almost clear)

Pruritus Patient‐reported itch severity NRS 0 = no symptoms; 10 = worst imaginable symptoms

NRS = Numerical Rating Scale; SCORAD = SCOring Atopic Dermatitis; EASI = Eczema Area and Severity Index. Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35–50; Rehal B, Armstrong AW. PLoS One. 2011;6(4):e17520. © 2019 PRIME® Education, LLC. All Rights Reserved.. 55

Assessing the Burden of AD in Clinic

AAD guidelines recommend that clinicians ask general questions about itch, sleep, impact on daily activity, and persistence of disease • How long have you had your AD? • Is your AD active in bursts or tends to be active all the time? • Could you tell me how AD has affected you emotionally? • Could you tell me how AD has affected your sleep? • Could you tell me how AD has affected you at school or work? • Could you tell me how AD has affected your social life? • What are your goals for treatment of AD? • Could you tell me about the side effects that you have experienced from treatment for your AD, or that you are concerned about?

28 Therapeutic Management

AD Yardstick: Step‐Care Treatment and Management

Therapeutic Trial: Re‐assess AD control every 4 – 8 weeks for the first 3 months

Severe Basic Management Moderate & Referral to AD Specialist

Basic Management • Phototherapy Mild & Topical Anti‐Inflammatory • Dupilumab2 Non‐Lesional Medication • Immunosuppressants3 Basic Management • Corticosteroids4 Basic Management • Maintenance TCS, or • Consider acute treatment to gain • Skin care • Maintenance TCI, or control: • Skin care • Antiseptic measures • Crisaborole 2%1 . Wet wrap therapy • Trigger avoidance • Trigger avoidance . Short‐term hospitalization Maintenance

• Apply TCS (low to medium potency) to inflamed skin • Apply TCS (medium to high potency) to inflamed skin • If not resolved in 7 days, consider: . Non adherence, infection, misdiagnosis or contact allergy Acute . Referral to AD specialist/stepping up treatment

1Indicated for patients at least 2 years old with mild to moderate AD. 2Indicated for patients at least 18 years old with moderate to severe AD. 3Not approved by the Food and Drug Administration to treat AD. 4Approved by the Food and Drug Administration to treat AD but not recommended for long‐term maintenance. TCS = Topical Corticosteroids. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120(1):10–22.e2. © 2019 PRIME® Education, LLC. All Rights Reserved.. 58

29 Topical Corticosteroids

Use TCS when moisturizers and good skin care fail • Acute treatment: once or twice daily application • Maintenance: intermittent application (1–2x weekly) on areas that commonly flare

Super‐potent Clobetasol Refractory lesions Betamethasone Tough‐to‐treat areas (e.g., hands, feet) Fluocinonide Mid‐potent Triamcinolone Mometasone Work‐horse of management Desonide Low‐potent Alclometasone Delicate skin areas (e.g., face, axillae, genitals) Hydrocortisone Mild eczema

TCS: Adverse Events

Systemic absorption can be clinically significant when used on extensive body surface area • Atrophy: . Hypopigmentation or skin lightening . Thinning and increased skin fragility . Poor wound healing . Stretch marks • Steroid phobia may result in poor adherence

30 Topical Calcineurin Inhibitors (TCIs)

Recommended as a steroid‐sparing agent for acute and chronic AD, with particular use at sensitive skin areas Not FDA approved for ages <2 years • Efficacy compared with other AD treatments: . Pimecrolimus 1% cream: • Comparable efficacy to low‐potency TCS . Tacrolimus 0.03% ointment: • Superior to pimecrolimus and low‐potency TCS . Tacrolimus 0.1% ointment: • Superior to tacrolimus 0.03%, pimecrolimus and low‐potency TCS • Equivocal in comparison with mid‐potency TCS . Slower onset of action than TCS

TCIs: Adverse Events

• May cause skin burning and pruritus: . Worse on wet skin • Boxed warning in 2006 for a possible risk of cancer: . 10‐year post‐marketing registries have not found danger signals related to cutaneous or extra‐cutaneous malignancies . Nevertheless, patients are commonly bothered by the “black‐box” warning

Elidel® (pimecrolimus) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America, LLC; August 2014; Protopic® (tacrolimus) [package insert]. Deerfield, IL: Astellas Pharma US, Inc; November 2011. © 2019 PRIME® Education, LLC. All Rights Reserved.. 62

31 How is Treatment Failure Defined in AD?

• No standard definition of treatment failure in AD • Treatment failure may be defined as one or more of the following: . Inadequate clinical improvement . Failure to achieve stable long‐term disease control . Presence of ongoing impairment (e.g., pruritus, pain, loss of sleep, and poor QoL) . Unacceptable adverse events or poor treatment tolerability • No generalizable time to demonstrate the efficacy of TCSs and TCIs . Up to 4 weeks for active appropriate treatment based on severity . In selected patients and specific body sites, >4 weeks may be necessary • No acceptable biomarkers to predict treatment response

Considerations for Stepping Up Treatment

Mild ↗ Moderate Moderate ↗ Severe • Inadequate control despite: • Inadequate control despite: . Appropriate use of low to medium potency TCS . Aggressive course of topical prescription therapy (TCS, TCI, . Basic management recommendations crisaborole) for ≥3 weeks . Basic management recommendations + trigger avoidance . Trigger avoidance • Consider if there is significant & negative impact on: • Options for stepping up treatment . Daily activities . Increase TCS dose or potency . Psychosocial health . Add TCI . Quality of life . Add crisaborole ointment • Options: Therapeutic trial: . Dupilumab . Phototherapy Re‐assess AD control at 4 – 8 weeks . Systemic immunosuppressants* for the first 3 months

*Not approved by the Food and Drug Administration to treat AD. TCS= topical corticosteroid; TCI = topic calcineurin inhibitor. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018 Jan;120(1):10‐22.e2. © 2019 PRIME® Education, LLC. All Rights Reserved.. 64

32 Evolving Landscape of AD Treatment and Management

FDA APPROVED Phase 3

Tralokinumab Tacrolimus Baricitinib IL‐13 inhibitor JAK 1/2 inhibitor Calcineurin inhibitors

Upadacitinib PF‐04965842 JAK 1 inhibitor JAK 1 inhibitor Dupilumab Topical Pimecrolimus IL‐4/IL‐13 inhibitor Phase 2 Corticosteroids Calcineurin inhibitors Lebrikizumab JAK inhibitors IL‐13 inhibitor

Crisaborole Nemolizumab ZPL389 PDE4 inhibitor IL‐31 R‐A inhibitor H4 receptor inhibitor

Tezepelumab MOR106 TSLP inhibitor IL‐17C inhibitor

Fezakinumab ANB020 IL‐22 inhibitor IL‐33 inhibitor

1960 2000 2001 2016 2017 Management historically focused on symptom relief vs new era of treatment targeting underlying inflammation

Key Inflammatory Processes in AD

Skin Barrier Allergens and Pathogens Itching • Immune abnormalities: Filaggrin LC TSLP . T‐helper cell dysregulation Naïve IL‐31 AMPs . Mast cell hyperactivity, Mast T‐Cell basophils, and eosinophils Cell IL‐4 ILC2 . IgE production (may be Th2 secondary) IL‐4 IL‐13 • Imbalance in T‐cell subsets: IgE B . Th2 cells predominate IL‐31 . Th2 cytokines: IL‐4, IL‐5, IL‐13 • Key player IL‐4? IL‐13? Or both? IL‐5 IL‐4 • IL‐5: Eos/ IL‐5 . IL‐5 is responsible for Blood Baso eosinophilia Vessel

IL = Interleukin; Th = T Helper; Eos = Eosinophils; Baso = Basophils; AMP = Antimicrobial Peptide; LC = Langerhans Cells; ILC = Innate Lymphoid Cells. Howell MD, et al. Allergy. 2015;70(8):887–896; Kim JE, et al. Int J Mol Sci. 2016;17(8):e1234. © 2019 PRIME® Education, LLC. All Rights Reserved.. 66

33 On‐Label and Off‐Label Systemic Therapies in AD

Drug Approved Estimated efficacy Dose range Common or serious side Monitoring for AD (% reduction in composite effects required (Y/N) severity scores) Azathioprine N 26–39% Adult: 1–3 mg/kg/day Hematologic abnormalities, CBC, CMP, Pediatric: 1–4 mg/kg/day malignancies, hepatosplenic thiopurine lymphoma, CNS infections methyl‐ transferase Cyclosporine N–US 53–95% Adult and pediatric: Renal insufficiency, CBC, CMP, Y–Europe 2.5–5 mg/kg hypertension, and drug magnesium, uric interactions acid, lipids, BP Methotrexate N 42% Adult: 7.5–25 mg/week Hepatotoxicity, hematologic CBC, CMP Pediatric: 0.2–0.7 mg/kg/week abnormalities, teratogen, GI intolerance, nausea, fatigue Mycophenolate N Unknown Adult: 1–1.5 g orally twice/day GI, teratogen CBC, CMP Pediatric: 30–50 mg/kg/day Dupilumab Y 73% Adult: 600 mg loading followed Injection site reactions, None by 300 mg every 2 weeks conjunctivitis

CBC = Complete Blood Count; CMP = Comprehensive Metabolic Panel; BP = Blood Pressure; GI = Gastrointestinal. Simpson EL, et al. J Am Acad Dermatol. 2017;77(4):623–633. © 2019 PRIME® Education, LLC. All Rights Reserved.. 67

Crisaborole for Mild‐to‐Moderate AD Phase 3 Primary Outcome Two multicenter phase 3 studies of identical design Key inclusion criteria: ≥2 years old; ≥5% BSA involvement; ISGA score of mild (2) or moderate (3) Baseline Characteristics Patients Achieving Success at Day 29*

AD‐301 AD‐302 50 Crisaborole Vehicle Crisaborole Vehicle P = 0.038 P < 0.001 (n = 503) (n = 256) (n = 513) (n = 250) 40 Age groups (%) 32.8 31.4 2–6 yrs 32.2 30.5 33.7 37.2 30 7–11 yrs 30.8 28.5 26.7 28.4 25.4 12–17 yrs 24.1 26.2 24.6 22.8 18.0 ≥ 18 yrs 12.9 14.8 15.0 11.6 20 Baseline ISGA (%) Mild (2) 39.0 36.3 38.4 40.0 10

Moderate (3) 61.0 63.7 61.6 60.0 Proportion of Patients (%) n = 503 n = 256 n = 513 n = 250 % BSA 0 Mean 18.8 18.6 17.9 17.7 AD‐301 AD‐302 Range 5–95 5–90 5–95 5–90 Crisaborole Vehicle

*ISGA of 0 [clear] or 1 [almost clear] with ≥ 2 grade improvement from baseline. ISGA = Investigator's Static Global Assessment. Paller AS, et al. J Am Acad Dermatol. 2016;75(3):494–503.e6. © 2019 PRIME® Education, LLC. All Rights Reserved.. 68

34 Crisaborole: Phase 3 Results (cont’d)

A greater percentage of crisaborole‐treated patients achieved improvement in pruritus across all study visits Median time to improvement = 1.37 days active vs 1.73 days control (P = 0.001) 100

80 P < 0.001 P < 0.001 P < 0.001 P = 0.002 63 58 60 61 60

53 40 48 42 44

in Pruritus (%)* 20

0 Patients Achieving Improvement Baseline Day 8 Day 15 Day 22 Day 29

Crisaborole Vehicle

Crisaborole: Safety

• No treatment‐related serious AEs among patients treated with crisaborole: . Majority of AEs in crisaborole‐treated patients were mild • On a pooled basis, the rate of discontinuations due to AEs was 1.2% in patients treated with crisaborole compared with 1.2% in patients treated with vehicle • Treatment‐emergent AEs (≥2%) in pooled treatment groups

AD‐301 AD‐302 Pooled AEs Crisaborole Vehicle Crisaborole Vehicle Crisaborole Vehicle (n = 502) (n = 252) (n = 510) (n = 247) (n = 1,012) (n = 499)

Application site pain 6.2% 1.2% 2.7% 1.2% 4.4% 1.2%

URTI 2.8% 4.0% 3.1% 2.0% 3.0% 3.0%

35 Efficacy of Dupilumab Monotherapy in Adults with Moderate to Severe AD: SOLO 1/2 Phase 3 Results

IGA of 0 or 1 and ≥2 points ↓ from Baseline Pruritus in SOLO 1† at Week 16 (Primary End Point) Study Week 80 012345678910111213141516 70 0

*P <0.001 vs placebo

60 ‐10

* * * 50 * ‐20

40 ‐30 37.9 30 37.2 36.1 36.4 ‐40 Patients (%) ‐50 20

Pruritus NRS (%) ‐60 10 10.3 8.5 Change from Baseline ‐70 0 SOLO 1 SOLO 2 ‐80 Placebo QW Dupilumab 300 mg Q2W Dupilumab 300 mg QW

Efficacy of Dupilumab + TCS Treatment: Results from Two Phase 3 CHRONOS & CAFÉ Trials

CHRONOS CAFÉ Patients with Inadequate Response to TCS Patients with Inadequate Response or Intolerance to CSA IGA of 0 or 1 and ≥ 2 points EASI‐75 EASI‐75

Improvement from BL

80 80 * 80 * * 70 70 *

70 †

60 * 60 69 60 * * * 6465 64 50 50 50 58 57 40 40 40 30 39 39 40 30 30 36 Patients (%) Patients (%) 20 20 20 26 23 22 10 12 13 10 10 0 0 0 Wk 16 Wk 52 Wk 16 Wk 52 Wk 16 Placebo QW Dupilumab 300mg Q2W Dupilumab 300mg QW

*P ≤0.0001 vs placebo + TCS; †P < 0.0002 vs placebo + TCS. CSA = Cyclosporine A. Blauvelt A, et al. Lancet. 2017;389(10086):2287–2303; de Bruin‐Weller, et al. EADV 2017. Geneva, Switzerland. Presentation D3T01. © 2019 PRIME® Education, LLC. All Rights Reserved.. 72

36 Efficacy of Dupilumab Monotherapy in Adolescents: Results from the AD‐1526 Phase 3 Trial

Co‐Primary Endpoints at Week 16 Peak Pruritis NRS Score from BL to Week 16

Placebo Dupi 300mg Q4W Dupi 200/300 mg Q2W Week 80 (n = 85) (n = 84) (n = 82) 012345678910111213141516 0 70 *P < 0.001 vs placebo ‐10

60 –19.0

* ‐20

50 *

‐30 40 *

42 ‐40 –45.5 30 * 38 ‐50 –47.9 20 24 ‐60 10 18 Placebo (n = 85) 28 Dupilumab 300 mg q4w (n = 84) 0 Dupilumab 200/300 mg q2w (n = 82) IGA 0 or 1 EASI‐75

Dupi = Dupilumab; BL = Baseline; EASI = Eczema Area And Severity Index; QOL = Quality of Life; NRS =Numerical Rating Scale. Simpson EL, et al. 27th EADV Congress, September 12–16, 2018. Paris, France. Abstract 4640; Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed 3/19/2019. © 2019 PRIME® Education, LLC. All Rights Reserved.. 73

Dupilumab: Long‐term Safety

CHRONOS Phase 3 Results: Week 52 Placebo QWK Dupilumab 300 mg Q2W Dupilumab 300 mg QWK + TCS + TCS + TCS Event, n (%) (n = 315) (n = 110) (n = 315) ≥1 AE 226 (84) 97 (88) 261 (83) ≥1 Serious AE 16 (5) 4 (4) 9 (3) Death 0 0 1* (<1) AEs leading to discontinuation 24 (8) 2 (2) 9 (3) AEs occurring in ≥5% of patients Nasopharyngitis 61 (19) 25 (23) 60 (19) URTI 32 (10) 11 (10) 43 (14) AD 144 (46) 20 (18) 52 (17) Injection site reaction 24 (8) 16 (15) 60 (19) Asthma 19 (6) 5 (5) 2 (1) Herpes infections 25 (8) 8 (7) 22 (7) Non‐herpetic skin infections 56 (18) 12 (11) 26 (8) Conjuctivitis 25 (8) 15 (14) 61 (19)

37 Providing Patients with Self‐Care and Adherence Support

Adherence: Main Barrier to Improving AD Patient Outcomes

Patient‐reported reasons for poor adherence:

Treatment Patient Others

•Messy •Forgot • Financial burden •Fear •Busy • Limited •Confusing •Shortage communication with • Difficult • Feeling better provider •Ineffective • Feeling worse

38 Strategies to Increase Adherence

Create a written Discuss side effects Reinforce treatment eczema action plan proactively goals and benefits

Set frequent follow‐ Compliance and care Refer patients to up visits and establish management programs support groups and open communication offered through health plans education workshops

Therapeutic Patient Education for AD Patients and Caregivers

• How treatment works • Potential side effects • Apply treatment • Coping with disease •Trigger factors • Timeline for treatment •Recognize flares • Improve quality of life • Chronic course of response • Use treatment plan • Communicate with disease • Efficacy and long‐term others about AD control • Who to contact during a flare Disease Treatment Practical Relational Knowledge Knowledge Skills Skills

Tailored to each patient based on age, culture, language, health literacy, and learning preferences

Ersser SJ and Nicol NH. Educational interventions for the management of children with dry skin. In Loden M and Maibach H (Eds.), Treatment of Dry Skin Syndrome‐The Art and Science of Moisturizers. Berlin, BB: Springer‐Verlag; 2012. Nicol NH and Ersser SJ. The role of the nurse educator in managing atopic dermatitis. In M. Boguniewicz (Ed.), Immunology and Allergy Clinics of North America: Atopic Dermatitis. Philadelphia, PA: Saunders‐Elsevier;2010; Boguniewicz, M, et al. Semin Cutan Med Surg. 2008;27(2):115–127; Brar K, et al. J Allergy Clin Immunol Pract. 2019;7(1):1–16; LeBovige J, et al. Semin Cutan Med Surg. 2017;36(3):131–136. © 2019 PRIME® Education, LLC. All Rights Reserved.. 78

39 Need for Individualized Written Treatment Plan

Written AD action plans assist with coordination of care and moving towards self‐care

Brar KK, et al. J Allergy Clin Immunol Pract. 2019; 7(1):1–16.

Engaging the Interprofessional Team Throughout the AD Care Cycle

Aspects of Long‐Term Management in AD • Proactive vs reactive management of flares • Consistent and proper skin care Disease assessment • Avoidance of triggers • Education and adherence support • Management of comorbidities and side effects Long‐term Treatment –Eye disorders monitoring PATIENT selection – Cardiovascular health – Systemic manifestations • Health maintenance Adherence –Diet and –Nutrition education –Exercise –Smoking status • Psychosocial issues/quality of life

LeBovidge JS, et al. J Allergy Clin Immunol. 2016;138(2):325–334; Sayaseng KY, Vernon P. J Pediatr Health Care. 2018;32(2):S2–S12; Eichenfield LF, et al. J Allergy Clin Immunology. 2017;139:S49–S57. © 2019 PRIME® Education, LLC. All Rights Reserved.. 80

40 Strategies to Improve Care Coordination in AD

Network to find physician groups to collaborate with • Visit physician groups in your area and establish contact • Attend hospital‐sponsored events and exchange cards • Find certified specialists through national organizations – AAD: find‐a‐derm.aad.org – ACAAI: acaai.org/locate‐an‐allergist Teledermatology is increasingly – AAAAI: allergist.aaaai.org/find becoming an option to meet the demand for dermatologic Use digital technology and online tools services, particularly in rural and • Online diagnostic tools (like www.visualdx.com) • eConsults (like www.rubiconmd.com) underserved communities. • Electronic referral networks • Teledermatology (traditional and direct‐access)

Stay in touch and maintain referral network • Follow up with all inbound/outbound referrals before and after visits • Say thank you and send personal invitations to them • Get feedback through physician liaison, surveys, or direct calls

Children’s Hospital Association. Improving communication between primary care providers and specialists. https://www.childrenshospitals.org/Newsroom/Childrens‐Hospitals‐ Today/Articles/2019/03/Improving‐Communication‐Between‐Primary‐Care‐Providers‐and‐Specialists. Accessed 8/22/19; AAD. Teledermatology: benefits and challenges. https://aadmeetingnews.org/2018‐ summer‐meeting‐wrap‐up/teledermatology‐benefits‐and‐challenges/. Accessed 8/22/19. © 2019 PRIME® Education, LLC. All Rights Reserved.. 81

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